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This online archive of the CDC Prevention Guidelines Database
is being maintained for historical purposes, and has had no new entries
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We thank the following persons/projects for contributing data used to
establish the CD4+ percent categories: Stephane Blanche, the French Colla-
borative Study; Mary Glenn Fowler, the Women and Infants Transmission Study;
Catherine Peckham, the European Collaborative Study; Margaret Heagarty, the
New York City Perinatal HIV Transmission Collaborative Study; Savita Pahwa,
North Shore University Hospital; and William Shearer and Celine Hanson,
Baylor Medical Center.

Summary

This revised classification system for human immunodeficiency virus (HIV)
infection in children replaces the pediatric HIV classification system
published in 1987 (1). This revision was prompted by additional knowledge
about the progression of HIV disease among children.

In the new system, infected children are classified into mutually
exclusive categories according to three parameters: a) infection status, b)
clinical status, and c) immunologic status. The revised classification system
reflects the stage of the child's disease, establishes mutually exclusive
classification categories, and balances simplicity and medical accuracy in
the classification process. This document also describes revised pediatric
definitions for two acquired immunodeficiency syndrome-defining conditions.

INTRODUCTION

Following the initial report in 1982 of acquired immunodeficiency
syndrome (AIDS) in children (2), it became evident that the clinical charac-
teristics of AIDS in children were different from those in adults. In 1987,
CDC published a classification system for children infected with human
immunodeficiency virus (HIV) (1), the causative agent of AIDS. This classifi-
cation system categorized clinical manifestations of HIV infection in
children based on the limited data available early in the epidemic. New
knowledge about the progression of HIV disease among children warranted
revision of the 1987 classification system to better reflect the disease
process.

In 1991, CDC convened a working group of Public Health Service and other
consultants to discuss revision of the pediatric HIV classification system.
The 1994 revised classification system was developed through ongoing colla-
borations with the consultants following the 1991 meeting. The goal of the
working group was to construct a revised system that would:

reflect the stage of disease for an HIV-infected child (i.e., the child's
placement in the classification should have prognostic significance);

establish mutually exclusive classification categories; and

balance simplicity and medical accuracy in the classification process.

In the new system (Table 1), HIV-infected children are classified
into mutually exclusive categories according to three parameters: a)
infection status, b) clinical status, and c) immunologic status. Once
classified, an HIV-infected child cannot be reclassified in a less severe
category even if the child's clinical or immunologic status improves.

DIAGNOSING HIV INFECTION IN CHILDREN

Diagnosis of HIV infection in children born to HIV-infected mothers (Box
1 Table B1) is complicated by the presence of maternal anti-HIV IgG
antibody, which crosses the placenta to the fetus. Virtually all these
children are HIV-antibody positive at birth, although only 15%-30% are
actually infected. In uninfected children, this antibody usually becomes
undetectable by 9 months of age but occasionally remains detectable until 18
months of age. Therefore, standard anti-HIV IgG antibody tests cannot be used
to indicate reliably a child's infection status before 18 months of age (3).
Polymerase chain reaction (PCR) and virus culture are probably the most
sensitive and specific assays for detecting HIV infection in children born to
infected mothers (4-6). Use of these assays can identify approximately
30%-50% of infected infants at birth and nearly 100% of infected infants by
3-6 months of age (7).

The standard p24-antigen assay is less sensitive than either virus
culture or PCR, especially when anti-HIV antibody levels are high, because it
fails to detect immune-complexed p24 antigen (8). However, modification of
the p24-antigen assay to dissociate immune complexes has increased its
sensitivity in diagnosing HIV infection among children exposed to HIV (9).
Other laboratory assays (e.g., anti-HIV IgA and ELISPOT/in vitro antibody
production {IVAP}) have not been included in the algorithm for determining
infection status because they are not commonly used. In addition, they are
less sensitive than both PCR or virus culture. However, clinicians who
determine a child's antiretroviral therapy on the basis of such assays may
use them to classify the child as being infected.

Some children develop severe clinical conditions resulting from HIV
infection before their infection status has been sufficiently established.
For the purposes of classification, a child meeting the criteria for AIDS in
the 1987 case definition (10) should be considered HIV-infected -- even in
the absence of definitive laboratory assays.

Children born to mothers with HIV infection are defined as seroreverters
(SRs) and are considered uninfected with HIV if they a) become HIV-antibody
negative after 6 months of age, b) have no other laboratory evidence of HIV
infection, and c) have not met the AIDS surveillance case definition criteria
(Box 1 Table B1). Sufficient data are not available to conclusively
define a child who is uninfected on the basis of viral detection tests.
However, in certain situations (e.g., clinical trials), negative viral
detection tests may be used presumptively to exclude infection.

IMMUNOLOGIC CATEGORIES

The three immunologic categories (Table 2) were established to
categorize children by the severity of immunosuppression attributable to HIV
infection. CD4+ T-lymphocyte depletion is a major consequence of HIV
infection and is responsible for many of the severe manifestations of HIV
infection in adults. For this reason, CD4+ counts are used in the adult HIV
classification system (11). However, several findings complicate the use of
CD4+ counts for assessing immunosuppression resulting from HIV infection in
children. Normal CD4+ counts are higher in infants and young children than in
adults and decline over the first few years of life (12-16). In addition,
children may develop opportunistic infections at higher CD4+ levels than
adults (17-19). Although insufficient data exist to correlate CD4+ levels
with disease progression at all age groups, low age-specific CD4+ counts
appear to correlate with conditions associated with immunosuppression in
children (12,17,20,21). Therefore, despite these complications, classifi-
cation based on age-specific CD4+ levels appears to be useful for describing
the immunologic status of HIV-infected children.

Fewer data are available on age-specific values for CD4+ T-lymphocyte
percent of total lymphocytes than for absolute counts. However, the CD4+ T-
lymphocyte percent has less measurement variability than the absolute count
(22). To establish the age-specific values of CD4+ percent that correlate
with the CD4+ count thresholds, CDC compiled data from selected clinical
projects in the United States and Europe. The data included greater than
9,000 CD4+ counts, with the corresponding CD4+ percent determinations, from
both HIV-infected and uninfected children less than 13 years of age.
Nonparametric regression modeling was used to establish the CD4+ percent
boundaries that best correlated with the CD4+ count boundaries in the
classification system.

The immunologic category classification (Table 2) is based on either
the CD4+ T-lymphocyte count or the CD4+ percent of total lymphocytes. If both
the CD4+ count and the CD4+ percent indicate different classification
categories, the child should be classified into the more severe category.
Repeated or follow-up CD4+ values that result in a change in classification
should be confirmed by a second determination. Values thought to be in error
should not be used. A child should not be reclassified to a less severe
category regardless of subsequent CD4+ determinations.

CLINICAL CATEGORIES

Children infected with HIV or perinatally exposed to HIV may be
classified into one of four mutually exclusive clinical categories based on
signs, symptoms, or diagnoses related to HIV infection (Box 2 Table B2).
As with the immunologic categories, the clinical categories have been defined
to provide a staging classification (e.g., the prognosis for children in the
second category would be less favorable than for those in the first
category).

Category N, not symptomatic, includes children with no signs or symptoms
considered to be the result of HIV infection or with only one of the
conditions listed in Category A, mildly symptomatic. Category N was separated
from Category A partly because of the substantial amount of time that can
elapse before a child manifests the signs or symptoms defined in Category B,
moderately symptomatic. Also, more staging information can be obtained during
this early stage of disease by separating Categories N and A. In addition,
for children who have uncertain HIV-infection status (prefix E), Categories
N and A may help to distinguish those children who are more likely to be
infected with HIV (23) (i.e., children in Category EA may be more likely to
be infected than children in Category EN).

Category B includes all children with signs and symptoms thought to be
caused by HIV infection but not specifically outlined under Category A or
Category C, severely symptomatic. The conditions listed in Box 2 Table B2
are examples only; any other HIV-related condition not included in Category
A or C should be included in Category B. Anemia, thrombocytopenia, and
lymphopenia have defined thresholds in the new classification system (23).
Category C includes all AIDS-defining conditions except lymphoid inter-
stitial pneumonitis (LIP) (Box 3 Table B3). Several reports indicate that
the prognosis for children with LIP is substantially better than that for
children who have other AIDS-defining conditions (21,24,25). Thus, LIP has
been separated from the other AIDS-defining conditions in Category C and
placed in Category B.

Signs and symptoms related to causes other than HIV infection (e.g.,
inflammatory or drug-related causes) should not be used to classify children.
For example, a child with drug-related hepatitis or anemia should not be
classified in Category B solely because these conditions may be associated
with HIV infection. In contrast, a child with anemia or hepatitis should be
classified in Category B when the condition is thought to be related to HIV
infection. The criteria for diagnosing some conditions and determining
whether a child's signs, symptoms, or diagnoses are related to HIV infection
may not be clear in all cases, and therefore may require judgment of the
clinicians and researchers using the classification system.

Categories in the 1987 pediatric HIV classification system can be
translated into categories in the 1994 system in most cases (Box 4
Table B4). Class P0 is now designated by the prefix "E," and Class P1 is
now Class N. Children previously classified as P2A are now classified in more
than one category, reflecting the different prognoses for children with
different conditions included in the P2A category (e.g., children who have
wasting syndrome have a worse prognosis than those who have lymphadenopathy).

EFFECT ON THE AIDS SURVEILLANCE CASE DEFINITION FOR CHILDREN

Because the classification system is used in conjunction with the AIDS
case definition, the 1994 revision provided an opportunity to update certain
features of the 1987 AIDS surveillance case definition for children less than
13 years of age (10). Although LIP is in Category B under the new pediatric
HIV classification system, it will continue to be reportable to state and
local health departments (along with the conditions in Category C) as an
AIDS-defining condition in children. Two changes in the definitions for other
conditions are summarized in the following bulletted text:

The new definitions for HIV encephalopathy and HIV wasting syndrome
reflect increased knowledge of these conditions in children and replace
the definitions published in the 1987 AIDS surveillance case definition
for children. The definition of HIV en-cephalopathy follows the recom-
mendations of the American Academy of Neurology AIDS Task Force (26).
Because this condition is complex, diagnosis may require neurologic
consultation.

The new definition of HIV infection (Box 1 Table B1) replaces the
definition for laboratory evidence of HIV infection in children used in
the 1987 pediatric AIDS case definition. For children with an AIDS-
defining condition that requires laboratory evidence of HIV infection, a
single positive HIV-detection test (i.e., HIV culture, HIV PCR, or HIV
antigen {p24}) is sufficient for a reportable AIDS diagnosis if the
diagnosis is confirmed by a clinician.

References

CDC. Classification system for human immunodeficiency virus (HIV)
infection in children under 13 years of age. MMWR 1987;36:225-30,235.

Simpson BJ, Andiman WA. Difficulties in assigning human immunodeficiency
virus-1 infection and seroreversion status in a cohort of HIV-exposed
children using serologic criteria established by the CDC and Prevention.
Pediatrics 1994;93:840-2.

Denny T, Yogev R, Gelman R, et al. Lymphocyte subsets in healthy children
during the first 5 years of life. JAMA 1992;267:1484-8.

McKinney RE, Wilfert CM. Lymphocyte subsets in children younger than 2
years old: normal values in a population at risk for human immunode-
ficiency virus infection and diagnostic and prognostic application to
infected children. Pediatr Infect Dis J 1992;11:639-44.

The European Collaborative Study. Age-related standards for T-lymphocyte
subsets based on uninfected children born to human immunodeficiency
virus-1-infected women. Pediatr Infect Dis J 1992;11:1018-26.

Working Group of the American Academy of Neurology AIDS Task Force.
Nomenclature and research case definitions for neurologic manifestations
of human immunodeficiency virus-type 1 (HIV-1) infection. Neurology
1991;41:778-86

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Table B1

BOX 1. Diagnosis of human immunodeficiency virus (HIV) infection in children *
DIAGNOSIS: HIV INFECTED
a) A child <18 months of age who is known to be HIV seropositive or born to an
HIV-infected mother and:
. has positive results on two separate determinations (excluding cord blood)
from one or more of the following HIV detection tests:
-- HIV culture,
-- HIV polymerase chain reaction,
-- HIV antigen (p24),
or
. meets criteria for acquired immunodeficiency syndrome (AIDS) diagnosis
based on the 1987 AIDS surveillance case definition (10).
b) A child >=18 months of age born to an HIV-infected mother or any child
infected by blood, blood products, or other known modes of transmission (e.g.,
sexual contact) who:
. is HIV-antibody positive by repeatedly reactive enzyme immunoassay (EIA)
and confirmatory test (e.g., Western blot or immunofluorescence assay
{IFA});
or
. meets any of the criteria in a) above.
DIAGNOSIS: PERINATALLY EXPOSED (PREFIX E)
A child who does not meet the criteria above who:
. is HIV seropositive by EIA and confirmatory test (e.g., Western blot or
IFA) and is <18 months of age at the time of test;
or
. has unknown antibody status, but was born to a mother known to be infected
with HIV.
DIAGNOSIS: SEROREVERTER (SR)
A child who is born to an HIV-infected mother and who:
. has been documented as HIV-antibody negative (i.e., two or more negative
EIA tests performed at 6-18 months of age or one negative EIA test after
18 months of age);
and
. has had no other laboratory evidence of infection (has not had two
positive viral detection tests, if performed);
and
. has not had an AIDS-defining condition.
* This definition of HIV infection replaces the definition published in the 1987
AIDS surveillance case definition (10).

Table B2

BOX 2. Clinical categories for children with human immunodeficiency virus (HIV)
infection
CATEGORY N: NOT SYMPTOMATIC
Children who have no signs or symptoms considered to be the result of HIV
infection or who have only one of the conditions listed in Category A.
CATEGORY A: MILDLY SYMPTOMATIC
Children with two or more of the conditions listed below but none of the condi-
tions listed in Categories B and C.
-- Lymphadenopathy (>=0.5 cm at more than two sites; bilateral = one site)
-- Hepatomegaly
-- Splenomegaly
-- Dermatitis
-- Parotitis
-- Recurrent or persistent upper respiratory infection, sinusitis, or otitis
media
CATEGORY B: MODERATELY SYMPTOMATIC
Children who have symptomatic conditions other than those listed for Category
A or C that are attributed to HIV infection. Examples of conditions in clinical
Category B include but are not limited to:
-- Anemia (<8 gm/dL), neutropenia (<1,000/mm3), or thrombocytopenia
(<100,000/mm3) persisting >=30 days
-- Bacterial meningitis, pneumonia, or sepsis (single episode)
-- Candidiasis, oropharyngeal (thrush), persisting (>2 months) in children
>6 months of age
-- Cardiomyopathy
-- Cytomegalovirus infection, with onset before 1 month of age
-- Diarrhea, recurrent or chronic
-- Hepatitis
-- Herpes simplex virus (HSV) stomatitis, recurrent (more than two episodes
within 1 year)
-- HSV bronchitis, pneumonitis, or esophagitis with onset before 1 month of
age
-- Herpes zoster (shingles) involving at least two distinct episodes or more
than one dermatome
-- Leiomyosarcoma
-- Lymphoid interstitial pneumonia (LIP) or pulmonary lymphoid hyperplasia
complex
-- Nephropathy
-- Nocardiosis
-- Persistent fever (lasting >1 month)
-- Toxoplasmosis, onset before 1 month of age
-- Varicella, disseminated (complicated chickenpox)
CATEGORY C: SEVERELY SYMPTOMATIC
Children who have any condition listed in the 1987 surveillance case definition
for acquired immunodeficiency syndrome (10), with the exception of LIP (Box 3).

Table B3

BOX 3. Conditions included in clinical Category C for children infected with human
immunodeficiency virus (HIV)
CATEGORY C: SEVERELY SYMPTOMATIC *
-- Serious bacterial infections, multiple or recurrent (i.e., any combination of
at least two culture-confirmed infections within a 2-year period), of the
following types: septicemia, pneumonia, meningitis, bone or joint infection,
or abscess of an internal organ or body cavity (excluding otitis media, super-
ficial skin or mucosal abscesses, and indwelling catheter-related infections)
-- Candidiasis, esophageal or pulmonary (bronchi, trachea, lungs)
-- Coccidioidomycosis, disseminated (at site other than or in addition to lungs
or cervical or hilar lymph nodes)
-- Cryptococcosis, extrapulmonary
-- Cryptosporidiosis or isosporiasis with diarrhea persisting >1 month
-- Cytomegalovirus disease with onset of symptoms at age >1 month (at a site
other than liver, spleen, or lymph nodes)
-- Encephalopathy (at least one of the following progressive findings present for
at least 2 months in the absence of a concurrent illness other than HIV
infection that could explain the findings): a) failure to attain or loss of
developmental milestones or loss of intellectual ability, verified by standard
developmental scale or neuropsychological tests; b) impaired brain growth or
acquired microcephaly demonstrated by head circumference measurements or brain
atrophy demonstrated by computerized tomography or magnetic resonance imaging
(serial imaging is required for children <2 years of age); c)acquired
symmetric motor deficit manifested by two or more of the following: paresis,
pathologic reflexes, ataxia, or gait disturbance
-- Herpes simplex virus infection causing a mucocutaneous ulcer that persists for
>1 month; or bronchitis, pneumonitis, or esophagitis for any duration
affecting a child >1 month of age
-- Histoplasmosis, disseminated (at a site other than or in addition to lungs or
cervical or hilar lymph nodes)
-- Kaposi's sarcoma
-- Lymphoma, primary, in brain
-- Lymphoma, small, noncleaved cell (Burkitt's), or immunoblastic or large cell
lymphoma of B-cell or unknown immunologic phenotype
-- Mycobacterium tuberculosis, disseminated or extrapulmonary
-- Mycobacterium, other species or unidentified species, disseminated (at a site
other than or in addition to lungs, skin, or cervical or hilar lymph nodes)
-- Mycobacterium avium complex or Mycobacterium kansasii, disseminated (at site
other than or in addition to lungs, skin, or cervical or hilar lymph nodes)
-- Pneumocystis carinii pneumonia
-- Progressive multifocal leukoencephalopathy
-- Salmonella (nontyphoid) septicemia, recurrent
-- Toxoplasmosis of the brain with onset at >1 month of age
-- Wasting syndrome in the absence of a concurrent illness other than HIV
infection that could explain the following findings: a) persistent weight loss
>10% of baseline OR b) downward crossing of at least two of the following
percantile lines on the weight-for-age chart (e.g., 95th, 75th, 50th, 25th,
5th) in a child >=1 year of age OR c) <5th percentile on weight-for-height
chart on two consecutive measurements, >=30 days apart PLUS a) chronic
diarrhea (i.e., at least two loose stools per day for >30 days) OR b)
documented fever (for >=30 days, intermittent or constant)
* See the 1987 AIDS surveillance case definition (10) for diagnosis criteria.